Inhibition of human squalene monooxygenase by tellurium compounds: evidence of interaction with vicinal sulfhydryls

Squalene monooxygenase is a flavin adenine dinucleotide-containing, microso mal enzyme that catalyzes the second step in the committed pathway for chol esterol biosynthesis, Feeding weanling rats a diet containing 1% elemental tellurium causes a transient, peripheral demyelination due to the disruptio n of cholesterol synthesis in Schwann cells secondary to inhibition of squa lene monooxygenase, The tellurium species responsible for the inhibition is unknown, as is the mechanism of inhibition. To study the potential mechani sms of tellurium toxicity in humans, three likely in vivo metabolites of te llurium (tellurite, dimethyltellurium dichloride, and dimethyltelluride) we re tested as inhibitors of purified human squalene monooxygenase, All three inhibitors reacted with the enzyme slowly and the resulting interaction wa s not freely reversible. The 50% inhibitory concentration for the methyltel lurium compounds (similar to 100 nM) after a 30-min preincubation was 100-f old lower than that of tellurite, indicating a role for hydrophobicity in t he enzyme-inhibitor interaction. The ability of glutathione and 2,3-dimerca ptopropanol to prevent and reverse the inhibition indicated that the tellur ium compounds were reacting with sulfhydryls on squalene monooxygenase, and the ability of phenylarsine oxide, which reacts specifically with vicinal sulfhydryls, to inhibit the enzyme indicated that these sulfhydryls are loc ated proximal to one another on the enzyme. These results suggest that the unusual sensitivity of squalene monooxygenase to tellurium compounds is due to the binding of these compounds to vicinal cysteines, and that methylati on of tellurium in vivo may enhance the toxicity of tellurium for this enzy me.